Alzheimer's disease (AD) is characterized by a progressive loss of cognitive function and constitutes the most common and fatal neurodegenerative disorder. Genetic and clinical evidence supports the hypothesis that accumulation of amyloid deposits in the brain plays an important role in the pathology of the disease. This event is associated with perturbations of biological functions in the surrounding tissue leading to neuronal cell death, thus contributing to the disease process. The deposits are composed primarily of amyloid (Aβ) peptides, typically a 39-43 amino acid sequence that self aggregates into a fibrillar β-pleated sheet motif. While the exact three-dimensional structure of the aggregated Aβ peptides is not known, a model structure that sustains the property of aggregation has been proposed. This creates opportunities for in vivo imaging of amyloid deposits that not only can help evaluate the time course and evolution of the disease but can also allow the timely monitoring of therapeutic treatments.
Historically, Congo Red (CR) and Thioflavin T (ThT) have provided the starting point for the visualization of amyloid plaques and are still commonly employed in post mortem histological analyses. However, due to their charge these compounds are thought to be unsuitable for in vivo applications. To address this issue, several laboratories developed compounds with non charged, lipophilic (log P=0.1-3.5) and low molecular weight chemical structures (M.W. less than 650) that facilitate crossing of the blood brain barrier. Further functionalization of these compounds with radio-nuclides led to a new generation of in vivo diagnostic reagents that target plaques and related structures for imaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT), as known in the art.
Despite these advances, there is a pressing need for the design and development of new amyloid-targeting molecules with improved physical, chemical and biological characteristics. Provided herein are methods and compounds addressing these and other needs in the art.